Salts of n-phenyl-n-(2-pyridylmethyl)-2-(n-piperidino)-ethylamine

ABSTRACT

SALTS OF N-PHENYL-N-(2-PYRIDYLMETHYL)-2-(N-PIPERIDINO)-ETHYLAMINE WITH A SATURATED FATTY ACID HAVING 14 TO 22 CARBON ATOMS OR WITH HYDROXYPHENYL-BENZOYLBENZOIC ACID ARE ANTITUSSIVE AGENTS.

United States Patent 6 Claims ABSTRACT OF THE DISCLOSURE Salts of Nphenyl N-(Z-pyridylmethyl)-2-(N-piperidino)-ethylarnine with a saturatedfatty acid having 14 to 22 carbon atoms or withhydroxyphenyl-benzoylbenzoic acid are antitussive agents.

This invention relates to an organic acid salt of a picoline derivative,more particularly, to a pharmaceutically acceptable salt ofN-phenyl-N-(2-pyridylmethyl)-2- (N-piperidino)-ethylamine with anorganic acid, the acid being a saturated fatty acid of 14 to 22 carbonatoms or hydroxyphenylbenzoylbenzoic acid.

The salts of the invention are novel compounds and are useful asantitussive drugs. They are crystalline, tasteless, stable,non-hygroscopic and low in toxicity.

As a compound having antitussive action, there has previously been knownN-phenyl-N-(Z-pyridylmethyl)-2-(N- piperidino)-ethylamine. However, itis oily and subject to discoloration and, in addition, shows bitternesswith some unpleasant after-taste. Its hydrochloride, althoughcrystalline, still shows bitterness. Neither of these is, therefore,suitable for use as a powdery preparation.

The present invention is based upon the discovery that, among salts ofN-phenyl-N-(2-pyridylmethyl)-2- (N-piperidino)-ethy1amine was variousorganic acids, a salt with a saturated fatty acid having 14 to 22 carbonatoms or hydroxyphenylbenzoylbenzoic acid, which salts are easilycrystallizable, are suitable for use in pharmaceutical preparations.These salts are non-hygroscopic and sufficiently stable to afford longstorage, have no taste and possess low toxicity.

On the other hand, it was also confirmed by the present inventors thatsalts with a saturated fatty acid having 12 or less carbon atoms (e.g.lauric acid, capn'c acid, caprylic acid) are not crystalline; salts witha saturated fatty acid having 24 or more carbon atoms (e.g. lignocericacid) show a hemolytic action; salts with an unsaturated fatty acid(e.g. linoleic acid) are unstable; salts with aliphatic dicarboxy'licacids (e.g. maleic acid, "fumaric acid, citric acid) have a bittertaste; and salts with a large majority of aromatic carboxylic acid haveone or more faults such as being non-crystallizable, unstable and ofbitter taste.

A principal object of the present invention is toprovide organic acidsalts of N-phenyl-N-(2-pyridylmethyl)-2- (N- piperidino)-ethylaminewhich have an antitussive effect and the superior characteristics asmentioned above.

Another object of this invention is to provide a method for producingthe novel and useful organic acid salts of N phenyl N-(2-pyridy1methyl)-2-(N-piperidino)-ethylamine.

The new salts of this invention are conveniently prepared by reactingN-phenyl-N-(2-pyridylmethyl)-2- (N-piperidino)-ethylamine or a mineralacid salts thereof with a saturated fatty acid having 14 to 22 carbonatoms, hydroxyphenylbenzoylbenzoic acid, or a salt of either of them.

As the fatty acid having 14 to 22 carbon atoms there may be mentionedmyristic acid, palmitic acid, stearic acid, arachic acid, behenic acid,and the like. Salts of the fatty acids useful as starting materials areknown.

The starting materials to be employed in this invention areN-phenyl-N-(Z-pyridylmethyl) 2 (N piperidino)- ethylamine and itsmineral acid salts such as the hydrochloride and sulfate. When such amineral acid salt is employed, the fatty acid orhydroxyphenylbenzoylbenzoic acid is desirably reacted in the form of asuitable salt, such as an alkali or alkaline earth metal salt as, forinstance, the salts of sodium potassium, calcium or barium.

The reaction is preferably conducted in a suitable solvent which may beselected from among the organic solvents capable of dissolving thestarting material N-phenyl- N (2 pyridylmethyl)-2-(N-piperidino)-ethylamine, e.g. lower alcohols, acetone, acetic acidesters, and the like or mixtures of these with organic solvents whichare miscible with the first-mentioned solvents, e.g. ether, benzene,petroleum ether, chloroform, or with water. Among these, a mixed solventof lower alcohol and ethyl ether, as well as acetone, is particularlybeneficial.

The reaction usually proceeds at room temperature, but it may beconducted under heating, if required.

When the reaction is complete, crystals of the end product separate out.Therefore, those crystals may be separated from the mother liquor by,for example, filtration in a per se conventional manner. If the endproduct remains dissolved in the solvent, the product can be isolated bytreating the reaction mixture to obtain a concentrated solution and,then, by cooling the solution or by adding a solvent in which theproduct does not dissolve, so as to precipitate the end product. It isalso possible to isolate the end product by the use of ion exchangeresin. The reaction proceeds almost quantitatively.

The following experimental data show the properties of the compound ofthis invention.

EXPERIMENT 1 Stability test The test was made for examining changes incolor and hygroscopicity as to respective compounds.

No. 1 N-phenyl-N-(2-pyridylmethyl)-2- (N-piperidino)- ethylaminetri-palmitate No. 2 N-phenyl-N-(2-pyridylmethyl)-2-(N-piperidino)-ethylamine tri-stearate No. 3N-phenyl-N-(2-pyridylmethyl)-2-(N-piperidino)- ethylamine tri-myristateNo. 4 N-phenyl-N-(2-pyridylmethyl)-2-(N-piperidino)- ethylaminetri-behenate No. 5 N-phenyl-N-(2-pyridylmethyl)-2-(N-piperidin0)-ethylamine hydroxyphenylbenzoylbenzoate No. 6N-phenyl-N-(Z-pyridylmethyl)-2-(N-piperidino)- ethylamine (control) No.7 N-phenyl-N-(2-pyridylrnethyl)-2-(N-piperidino)- ethylaminehydrochloride (control) No. 8N-phenyl-N-(Z-pyridylmethyl)-2-(N-piperidino)- ethylamine tri-linoleate(control) (The above compounds will hereinafter be designated by therespective numbers.)

Conditions: 40 'C., relative humidity.

The above samples were allowed to stand under the above conditions andthe changes which they underwent With time were observed.

The results are shown in Table 1 (changes in color) and Table 2 (degreesof swelling).

TABLE 1.-CHANGES IN COLOR TABLE 4 Time (in days) Number of persons insensory response Compound Compounds of this invention:

No.1 10 I 0 0 NOTE: no change; a slight change; a fair change; aremarkable change.

TABLE 2.-])EGREE OF SWELLING Compound 3 7 NOTE: no change; a slightchange; a fair change; +++z a remarkable change.

It will be apparent from Tables 1 and 2 that whereas the controls No. 6,7 and 8 underwent coloration before the 14th day and, the controlcompound No. 7 underwent swelling at the 3rd day, none of the compoundsof this invention underwent coloration or swelling even after the lapseof 28 days.

EXPERIMENT 2 Antitussive test (in dog) A water suspension of a compoundwas administered to the stomach of a coughing and non-anesthetized dog(male, Weighing 8.5 kg.) through a tube previously put into the stomach,and antitussive dose (AtD was calculated by the Coughing Dog Method ofY. Kase Selected Pharmacological Testing Methods, 363 (A. Burger eds.),Marcel Dekker, Inc., New York (1969)]. The results are shown as follows:

Note: Figures in parentheses are the equivalent values as converted toCompound No. 6.

It will be seen from Table 3 that the compounds of this invention are aselfective as the starting material N0. 6 oh an equivalent basis (figuresin parentheses above are used for the former), and far superior to thecommercial preparations of Noscapine.

EXPERIMENT 3 Sensory test The powdery compounds were orally administeredto ten adults, and the bitterness with some remaining unpleasant tastewere evaluated.

NoTE: no perception at all; a slight perception; a fair 'perception;+++z a remarkable perception.

It will be seen from Table 4 that the compounds of this invention giveno bitterness with some remaining unpleasant taste at all, in contrastto the controls which produce extremely remarkable such bitterness.

EXPERIMENT 4 (a) Acute toxicity of compound No.7

Testing pr0cedure.-Compound No. 7 was administered orally orintravenously to groups each consisting of 10 male mice (ICRJCL/Tstrain, 4 weeks of age) and groups each consisting of 10 male rats(SD-JCL/T strain, 6 Weeks of age). The animals Were placed underobservation for 4 days, and 50% lethal dose (LD was calculated by theLitchfield-Wilcoxon method.

The results are shown in Table 5.

TABLE 5 LDso (mg/kg)... I.V. P.O.

011GB 9. 6 (8. (i) 195 (175.5) Rats 8.3 (7.5) 820 (738.0)

No'rE. -I.V. and P.O. signify intravenous injection" and "oraladministration. respectively. Figures in parentheses are the equivalentvalues as converted to compound No. 6.

(b) Acute toxicity of compound No. 1

Testing pr0cedure.Compound N0. 1 was administered intraperitoneally,subcutaneously or orally to groups each consisting of 10 mice (ICR-JCL/Tstrain, 4 weeks of age) and groups each consisting of 10 rats (SD-J CL/T strain, 6 weeks of age), and the animals were placed under observationfor 7 days, and 50% lethal dose (LD was calculated by theLitchfield-Wilcoxon method.

The results are shown in Table 6.

TABLE 6 Route of LD5 (mg/kg.) in mouse LDao (mg/kg.) in rat Male FemaleMale Female Nora 1.I.P. signifies intraperitioneal administration, S.C.subcutaneous injection and P.O. oral administration.

NOTE 2.Figures in parentheses denote the values as converted to compoundN o. 6.

It will be apparent from the above Tables 5 and 6 that the compounds ofthe present invention are less toxic than the compound No. 7.

Pharmaceutical compositions containing the salts of the presentinvention can be prepared according to any per se conventional methodfor the preparation of powders, tablets, capsules, syrups or injections.

When the compounds are used as antitussives, a daily dose as convertedto free base of about 10 to about 500 milligrams, generally about 50 toabout milligrams for adult, is advisable.

The present invention is further illustrated by the followingnon-limitative examples.

In these examples, part(s) means part(s) by weight unless otherwisespecified. Part(s) by weight bear the same relation to part(s) by volumeas do gram(s) to milliliter(s).

EXAMPLE 1 In parts by volume of ether is dissolved 1.5 parts ofN-phenyl-N-(2-pyridylmethyl)-2-(N-piperidino)-ethylamine, followed bythe addition of a solution of 4.2 parts of stearic acid in 60 parts byvolume of ether. The mixture is allowed to stand for a while and, then,concentrated whereupon colorless crystals separate. The crystals arerecovered by filtration and dried. The procedure yields 4.9 parts ofN-phenyl-N-(2-pyridylmethyl)-2-(N-piperidino)- ethylamine tri-stearatemelting at 5155 C.

Elementary analysis-Calculated for (percent): C, 76.32; H, 11.67; N,3.66. Found (percent): C, 75.92; H, 11.98; N, 3.69.

EXAMPLE 2 (percent): C, 75.58; H, 11.46; N, 3.95. Found (percent): C,75.48; H, 11.42; N, 3.91.

EXAMPLE 3 In 5 parts of volume of ether is dissolved 1.5 parts ofN-phenyl-N- 2-pyridylmethyl -2- (N-piperidino -ethylamine, followed bythe addition of a solution of 3.3 parts of myristic acid in 30 parts byvolume of ether.

After a While, the mixture is concentrated whereupon colorless crystalsseparate. The crystals are recovered by filtration and dried. Theprocedure yields 3.6 parts of the desired N phenyl N (2 pyridylmethyl) 2(N- piperidino)ethylarnine trimyristate which melts :at 48 to 51 C.

iElementary analysis-Calculated for (percent): C, 74.72; H, 11.20; N,4.29. Found (percent): C, 74.64; H, 11.48; N, 4.24.

EXAMPLE 4 In 5 parts by volume of ethanol is dissolved 1.5 part ofN-phenyl-N-(2-pyridylmethyl)-2-(N-piperidino)-ethylamine, followed bythe addition of a solution of 5.1 parts of behenic acid in 100 parts byvolume of ethanol, the ethanolic solution having been prepared at 50 C.The resulting mixture is stirred at 50 C. for a while and thenconcentrated, whereupon colorless crystals separate. Petroleum ether isadded, whereby 5.2 parts of N-phenyl- N (2 pyridylmethyl) 2 (Npiperidino) ethylamine tri-behenate is obtained. The product melts at74-76. C.

Elementary analysis-Calculated for (percent): C, 77.51; H, 12.01; N,3.19. Found (percent): C, 77.26; H, 11.86; N, 3.37.

EXAMPLE 5 In 25 parts by volume of ether is dissolved 8.0 parts ofN-phenyl-N-(2-pyridylmethyl)-2-(N-piperidino)-ethylamine, followed bythe addition of a solution of 8.1 parts of p-hydroxyphenylbenzoylbenzoicacid in a mixture of 300 parts by volume of ethanol and parts by volumeof acetone. The resulting mixture is concentrated, and petroleum etheris added. The resulting crystals are recovered by filtration, whereupon16.0 parts of the de sired N phenyl N (2 pyridylmethyl) 2 (N-piperidino) ethylamine p hydroxyphenylbenzoylbenzoate is obtained. Theproduct starts melting in the neighborhood of 90 C. and is completelymolten at C.

Elementary analysis-Calculated for (percent): C, 76.32; H, 6.41; N,6.85. Found (percent: C, 76.29; H, 6.51; N, 7.03.

What is claimed is:

1. A pharmaceutically acceptable salt of N-phenyl- N- 2-pyridylmethyl-2- (N-piperidino -ethylamine with a saturated fatty acid having 14 to22 carbon atoms or hydroxyphenylbenzoylbenzoic acid.

2. A compound as in claim 1 said compound being N phenyl N (2pyridylmethyl) 2 (N piperidino)- ethylamine tripalmitate.

3. A compound as in claim 1, said compound being N phenyl N (2pyridylmethyl) 2 (N piperidino)- ethylamine tristearate.

4. A compound as in claim 1, said compound being N phenyl N (2pyridylmethyl) 2 (N piperidino)- ethylamine trimyristate.

5. A compound as in claim 1, said compound being N phenyl N (2pyridylmethyl) 2 (N piperidino)- ethylamine tribehenate.

6. A compound as in claim 1, said compound being N phenyl N (2pyridylmethyl) 2 (N piperidino)- ethylaminep-hydroxyphenylbenzoylbenzoate.

References Cited Rericha et al., Chem. Listy 43, 176-9 (1949). [C.A.45.576h supplied; original unavailable].

JOHN D. RANDOLPH, Primary Examiner G. T. TODD, Assistant Examiner U.S.Cl. X.R.

